[unreadable] [unreadable] No treatment exists for any dominantly inherited neurodegenerative disease. In the dominant polyglutamine (polyQ) diseases expansion of a CAG triplet repeat results in a lengthened polyglutamine domain, conferring a dominant toxic property on the gene product. One promising strategy for therapy is therefore reduction of disease protein expression. Recent discoveries coupled with our own preliminary results suggest that small inhibitory RNA (siRNA) may be particularly effective in accomplishing this goal. In this proposal we will use spinocerebellar ataxia type I (SCAl), the best-characterized polyQ disorder, as our principal disease paradigm to test siRNA as a therapeutic approach. Neurodegeneration in SCAl is caused by CAG-repeat expansion in ataxin-1. Here, we will test the effect of siRNA in culture and animal models of SCA-1, which are perfectly suited to test the general therapeutic utility of this approach.